WO1996027303A1 - Article pour fumeurs exempt de nicotine - Google Patents

Article pour fumeurs exempt de nicotine Download PDF

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Publication number
WO1996027303A1
WO1996027303A1 PCT/US1996/002899 US9602899W WO9627303A1 WO 1996027303 A1 WO1996027303 A1 WO 1996027303A1 US 9602899 W US9602899 W US 9602899W WO 9627303 A1 WO9627303 A1 WO 9627303A1
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WO
WIPO (PCT)
Prior art keywords
cotinine
smoking
nicotine
subjects
smoking material
Prior art date
Application number
PCT/US1996/002899
Other languages
English (en)
Inventor
Robert M. Keenan
Original Assignee
Lectec Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lectec Corporation filed Critical Lectec Corporation
Priority to AU50918/96A priority Critical patent/AU5091896A/en
Publication of WO1996027303A1 publication Critical patent/WO1996027303A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/18—Treatment of tobacco products or tobacco substitutes
    • A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
    • A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances
    • A24B15/36—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring
    • A24B15/38—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring having only nitrogen as hetero atom
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/10—Chemical features of tobacco products or tobacco substitutes
    • A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed

Definitions

  • Cigarette smoking continues to be the major preventable cause of death in the United States resulting in nearly 400,000 deaths per year due to cancer and heart disease. Despite the potential adverse health effects, grave consequences, the vast majority of cigarette smokers are unable to cease smoking.
  • nicotine replacement e.g., via transdermal nicotine patches or nicotine gum is the most widely used. Nicotine gum decreases abstinence discomfort, especially anxiety, decreased memory and irritability. On the other hand, nicotine gum does not reliably decrease weight gain or craving. Also, discontinuing use of nicotine gum leads to some of the same symptoms as the cigarette withdrawal syndrome. Furthermore, nicotine is toxic, and the availability of nicotine gum or patches poses a risk of poisoning to children and pets.
  • alpha-2 agonists such as clonidine
  • decrease postcessation anxiety decrease postcessation anxiety
  • irritability decreases the mechanism by which these drugs decrease abstinence effects.
  • tobacco abstinence has some effects that could be attributed to sympathetic activity, it lacks the typical signs and symptoms of sympathetic overactivity, such as tachycardia, diaphoresis and hypertension.
  • the mechanism by which alpha-2 agonists exert their effects is unclear. While a number of other pharmacological treatments, such as use of doxepin, ACTH, and corticotrophins. for abstinence symptoms have been tested, none of the studies reported baseline and postcessation values for abstinence symptoms.
  • the present invention provides a smoking material that comprises pharmacologically-effective amount of cotinine or a pharmaceutically-acceptable salt thereof.
  • the amount of cotinine or the cotinine salt which is combined with the smoking material is preferably selected so that a human who smokes said material in a conventional manner, or who chews the material in the form of a "smokeless tobacco,” will inhale or ingest an amount of cotinine that is effective to (a) alleviate at least one of the symptoms of the tobacco withdrawal syndrome (TWS), (b) alleviate the similar abstinence effects due to cessation of nicotine, or (c) decrease smoking behavior, i.e.. tobacco consumption.
  • TWS tobacco withdrawal syndrome
  • a human subject attempting to remain abstinent from smoking, or to decrease smoking behavior, could smoke or chew the present smoking material to reduce his or her dependence on nicotine, or need to smoke or otherwise consume tobacco.
  • the uncomfortable symptoms of TWS or of nicotine withdrawal can be effectively counteracted, while the subject receives the oral gratification of smoking.
  • the symptoms of both tobacco and nicotine withdrawal are similar and are art recognized to include craving for nicotine, anxious/tense, irritable/angry, insomnia, impatience, restlessness, difficulty concentrating, increased eating, headache, excess hunger, somatic symptoms, weight gain and drowsiness.
  • the present invention also provides a therapeutic method to alleviate the craving for cigarettes, tobacco and/or nicotine that is associated with cessation of tobacco or nicotine use, e.g., by chewing or smoking, by the administration by smoking of an effective amount of cotinine or a pharmaceutically acceptable salt thereof, to a human in need of such treatment.
  • the present invention is also useful to treat the symptoms of nicotine withdrawal which are due. for example, to cessation of use of nicotine gum or a nicotine transdermal patch.
  • the present method is effective both to alleviate the TWS acutely and to permit patients to maintain abstinence from nicotine for extended periods of time.
  • the present method is also effective to decrease smoking behavior.
  • Cotinine has many qualities which can enhance its value as a smoking cessation aid. Cotinine has a long in vivo half-life, complete oral bioavailability, minimal effect on the cardiovascular system, and has not been reported to be harmful even at very high doses in many species including man. Also, because cotinine has no significant effect on the heart, a combined pharmacologic treatment approach using cotinine and nicotine may be possible, as by the application of cotinine to low-nicotine tobacco.
  • the present invention also provides an article of manufacture comprising packaging material, such as a box or envelope and the like; a smoking material contained within said packaging material, wherein said smoking material comprises cotinine or a pharmaceutically acceptable salt thereof in an amount effective to alleviate the tobacco withdrawal syndrome or the symptoms of nicotine withdrawal, and wherein said packaging material includes instruction means which indicate that said cotinine or said pharmacologically acceptable salt thereof can be used for alleviating tobacco withdrawal syndrome, or the symptoms of nicotine withdrawal.
  • Suitable instruction means include printed labels, printed package inserts, tags, and the like.
  • the smoking material is contained within a cigarette, cigar or is a shaped unit of a chewable vegetable material, such as a "chewing tobacco.”
  • the smoking material is preferably nicotine-free.
  • Figure 1 depicts the Minnesota Withdrawal Symptom Checklist.
  • Figure 2 is a graph depicting mean blood cotinine levels of the test subjects.
  • Figure 3 is a graph depicting the odds ratio of no irritability to severity by dosage.
  • Figure 4 is a graph depicting the odds ratio of no anxiety to some anxiety by dosage.
  • Figure 5 is a graph depicting the odds ratio of no difficulty concentrating to level experienced.
  • Figure 6 is a graph depicting odds of experiencing no impatience to some impatience.
  • Figure 7 is a graph depicting odds ratio of no increased appetite to level experienced.
  • Figure 8 is a graph depicting the change in the total withdrawal symptom score.
  • Cotinine (l-methyl-5-(3-pyridinyl)-2-pyrrolidinone) has the formula shown below:
  • the physiologically active form is the (-)-isomer. so as used herein, the term "cotinine” includes (-)-cotinine, or the racemic form, ( ⁇ )- cotinine.
  • the free base depicted above, can be employed in the practice of the invention, as can the pharmaceutically acceptable salts. These include the amine-acid addition salts of nontoxic organic acids or inorganic acids, such as the tartarate, fumarate ("scotine"), citrate, maleate, malate, hydrobromide. hydrochloride. sulfate, phosphate and the like. For example, see F. Vaitekunas, J. Amer. Che . Soc.. ___, 149 (1957). E.R.
  • cotinine has a relatively long terminal elimination half-life (two versus sixteen hours, respectively). Due to this pharmacological characteristic, cotinine has become the principally used objective biochemical marker of nicotine exposure in cigarette smoking and/or cessation-related research paradigms.
  • the present invention is based on the ability of cotinine to be self-administered in pharmacologically-effective amounts by inhalation of thermally-vaporized cotinine, as by smoking.
  • Smoking is generally defined as the act of inhaling the fumes of burning plant material, and pre-treatment of the plant material to coat or impregnate it with cotinine can result in the delivery of a therapeutical ly-effective amount of cotinine to the user.
  • smoking material effective as a carrier for the cotinine include nicotine-free tobacco. THC-free hemp, spices such oregano.
  • sassafras sage, spice- bush, clove and the like, grains, bark, leaves, cellulose, wood pulp, paper, and mixtures thereof.
  • Other adjuvants conventionally employed in tobacco or tobacco substitutes can also be added, including binders, aroma modifiers, sweeteners, flavorings and fillers. These include minor but effective amounts of glycerol, citric acid, sugars, malic acid, fruit juice, honey, vanilla extract, cinnamon, anise, cloves, cellulose derivatives, calcium carbonate, nitrate zeolite salts, and the like.
  • patents which disclose modified tobacco or vegetable-based non-tobacco smoking materials include U.S. Patent Nos.
  • the smoking material is preferably coated or impregnated with cotinine or a volatile salt thereof, for example, by infusing it or by spraying an aqueous solution or alcoholic solution of the cotinine salt onto the smoking material and drying it. either before or after macerating or shredding it for shaping or packaging.
  • Cotinine or the cotinine salt can be provided to the extent of about 5-50 mg of cotinine or cotinine salt per gram of smoking materials (0.5- 5 wt-% of cotinine).
  • the smoking material is then smoked in a pipe by the user (about 5-20 g treated smoking material), or is formed into cigarettes (about 0.75-1.25 g), or cigars (about 5-20 g).
  • the smoker would self-administer about 1 -20 mg cotinine per gram of smoking material which is consumed.
  • a smoker who smokes 20 cigarettes per day would ingest about 100 mg-1.0 g of cotinine, resulting in an actual bioavailable dose of about 20-400 mg of cotinine.
  • a cotinine-treated cigarette, cigar, unit of smoking material and the like can be considered a pharmaceutical unit dosage form, effective to deliver a preselected amount of cotinine to the user.
  • a pack of cotinine-treated cigarettes, a box or package of cotinine-treated cigars, a tin or soft pack of tobacco treated with cotinine, and the like are "kits" as broadly defined herein, insofar as they also comprise instruction means related to the self-administration of cotinine therefrom in accord with the present method.
  • Example I Example I - Oral Administration of -Cotinine Fumarate
  • TWS tobacco withdrawal syndrome
  • the following double blind, placebo controlled study was conducted at the University of Minnesota. More specifically, the study was conducted to (1) determine the safety of various doses of cotinine fumarate; (2) determine blood cotinine concentrations attained from various doses of cotinine fumarate; and (3) determine effects of various doses of cotinine fumarate on withdrawal signs and symptoms including physiological and subjective symptoms.
  • the results of this study demonstrate the : (1 ) cotinine fumarate up to 160 mg is safe.
  • ECG electrocardiogram
  • Subjects were included if they: (a) smoked at least one pack of cigarettes/day for at least one year; (b) submitted a CO>10 ppm: and (c) were in good health (e.g., no history of myocardial infarction, angina pectoris, sustained or episodic cardia arrhythmias, symptomatic peripheral vascular disease) as verified by medical history, screening examination, and screening laboratory tests. Subjects were excluded if they: (a) required any form of regular psychotropic medication; (b) chronically used systemic steroids or antihistamines; (c) abused alcohol or any other recreational or prescription drug; (d) used any other tobacco products including smokeless tobacco. To maximize compliance and completion of the study, subjects were paid $700 for their participation.
  • Subjects were admitted to research ward at noon. During the first two days of the study, baseline measure were obtained while the subject smoked cigarettes on an ad libitum basis. Subjects were required to be abstinent from cigarettes beginning in the morning of the third day. All subjects were given placebo at this time to allow some clearance of nicotine. On the morning of the fourth day, subjects were given placebo or one of the following oral doses of cotinine fumarate: 40 mg, 80 mg, and 160 mg. Nine subjects were to be run per each condition. Doses of cotinine were tested in ascending order. The subjects who are assigned to placebo were interspersed across the active dose conditions so that the blind would be maintained. If no adverse effects were detected for a particular dose, then the next higher dose was tested with the next group of subjects.
  • Subjects were given one of the oral doses of cotinine fumarate/placebo for the next 3 days. Three days of cotinine dosing were chosen since the maximum tobacco withdrawal effects are observed during 24-72 hours of abstinence. See Hughes et al.. Res. Adv. in Alcohol & Drug Problems, J ⁇ , Kozlowski et al., eds., Plenum Pub. (1990) at pages 317-398. Beginning on the eighth day. all subjects were required to take placebo again for three more days. This placebo condition would allow observation of withdrawal signs and symptoms from cotinine fumarate.
  • Abstinence was confirmed by biochemical verification (e.g., alveolar carbon monoxide) obtained at random times three times/day, evenly distributed across the day. Weight (after voiding) in the hospital gown was recorded and a sleep scale completed every morning. See Table 2. Subjects were required to complete subjective measures at the same times in the morning and afternoon throughout the study. See Table 2. These measures included the Addiction Research Center Inventory (Martin, Sloan, Sapira and Jasinski, Clin. Pharmacol.
  • Subjects were also measured at these times for vitals (sitting and standing blood pressure and heart rate), skin temperature, respiratory rate, assessed for adverse events, and a 12-lead EKG was obtained. Caloric intake was carefully monitored throughout the study. Meals, similar to ones normally ingested by the subjects, were planned by the registered dietician who then supervised the careful measurement and preparation of all the foods eaten by the subjects. Meal and snack trays (foods of various macronutrients made available to the subjects all day) were returned to the kitchen where all uneaten food and beverages were remeasured after each meal, thereby all the eaten food was recorded by type and amount. Food content was later analyzed and calculated for daily amount of carbohydrate, protein, fat, and calories.
  • Caffeine intake was controlled and maintained at the same level throughout the study. The amount of caffeine intake allowed for each individual was based on the levels of intake prior to the study. Alcohol intake was prohibited. Serum nicotine/cotinine samples were obtained at noon throughout the study. On days 2 and 6, blood samples were obtained to measure corticosteroids. On days 7 and 10, routine lab tests were taken. An internist monitored the subjects for a period of 30 minutes after the subjects took the medication to assess for any signs of toxicity.
  • Subjects were exposed to smoking related cues on Days 2, 5 and 9 since tobacco withdrawal symptoms may be minimized in an inpatient hospital setting when all normal cues for smoking are minimal. This cue involved exposure to their own brand of cigarettes and ashtray. Subjects were asked to look at their cigarettes, ashtray and matches for 15 seconds, light their cigarettes for 5 seconds, observe their lit cigarettes for another 15 seconds, then extinguish their cigarettes. During the study, subjects are free to engage in activities provided by the unit. Their exposure to smoking related stimuli were minimized during these activities in order to maintain consistency in cue exposures across subjects.
  • (S)-Cotinine was synthesized and converted into its fumarate salt by the method of McKennis and Bowman, Biochemical Preparation, 1963, IQ, 36 (1963).
  • the crystalline material was purified and found to be greater than 98% pure with no nicotine contamination. This material was characterized by elemental analysis, proton and carbon NMR, gas chromatography. and DSC.
  • the drug substance was formulated into capsule dosage form at the Research Pharmacy at the University of Minnesota.
  • the doses prepared were placebo (0 mg) and 40 mg, 80 mg. and 160 mg of cotinine fumarate. These were tested for uniformity of content, stability and drug release rate by standard USP dissolution testing.
  • the doses were coded to assure a double blind clinical experiment and provided to the research staff as needed.
  • a repeated measures analysis was performed for the three days the subject was on medication. In addition to cotinine level and number of cigarettes smoked daily, the average score of the two baseline smoking days was used as covariate.
  • terms included in the regression model were an intercept, the three covariates, main effects for time of day, day on medication, medication dosage, and interaction of day on medication by medication dosage.
  • terms included in the logit or probit model were an intercept, the three covariates, main effects for time of day. medication dosage and day on medication.
  • Figures 3-7 show the cigarette withdrawal symptoms that showed significant differences across groups.
  • Fig. 3 For irritability/frustration/anger (Fig. 3), anxiety (Fig. 4). difficulty concentrating (Fig. 5) and impatience (Fig. 6), the 80 mg dose group scored experienced significantly less severe symptoms than the placebo group.
  • Fig. 3 For irritability, the odds were 2.6 times greater to experience no irritability than slight irritability, and 6.9 times greater to experience no irritability than mild to severe irritability.
  • Fig. 6 For anxiety, the odds were 2.6 times greater to experience no anxiety than any anxiety.
  • the odds were 4.3 times greater in experiencing no difficulty than to experience slight difficulty in concentrating and 18.5 times greater in experiencing no difficulty concentrating than to experience mild to severe difficulty concentrating.
  • the odds were 13.7 times greater to experience no impatience than to experience any impatience.
  • the 40 and 80 mg groups experienced significantly lower scores than placebo.
  • the odds were 2.7, 7.2 and 19.2 times greater in reporting no increased appetite than to have experienced slight, mild or moderate to severe increases in appetite, experienced slight, mild or moderate to severe increases in appetite, respectively.
  • the odds were 2.8, 7.9, and 22.4 times greater in experiencing no increased appetite than to have experienced slight, mild or moderate to severe increase in appetite, respectively.

Abstract

L'invention concerne un article pour fumeurs qui est utile pour aider à surmonter les symptômes associés à la privation de tabac, contenant une certaine quantité de cotinine ou d'un sel de celle-ci acceptable sur le plan pharmaceutique, en combinaison avec un matériau non toxique d'origine végétale, cette quantité étant suffisante pour diminuer ou éliminer au moins un des symptômes associés à la privation de tabac chez un utilisateur, fumant cet article.
PCT/US1996/002899 1995-03-06 1996-03-04 Article pour fumeurs exempt de nicotine WO1996027303A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50918/96A AU5091896A (en) 1995-03-06 1996-03-04 Nicotine-free smoking material

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US39852895A 1995-03-06 1995-03-06
US08/398,528 1995-03-06

Publications (1)

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WO1996027303A1 true WO1996027303A1 (fr) 1996-09-12

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AU (1) AU5091896A (fr)
WO (1) WO1996027303A1 (fr)

Families Citing this family (8)

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Publication number Priority date Publication date Assignee Title
US20060112965A1 (en) * 2003-08-11 2006-06-01 Whalen William F Chewing tobacco substitute containing cotinine
KR200412339Y1 (ko) * 2005-12-26 2006-03-27 이태수 니코틴 함량이 낮은 담배
US20110186062A1 (en) * 2010-02-01 2011-08-04 Carra Leah Hood Smoking risk reduction/reduction to quit/cessation aid
JP7292035B2 (ja) 2015-06-26 2023-06-16 アルトリア クライアント サーヴィシーズ リミテッド ライアビリティ カンパニー アルカロイドレベル改変タバコ植物体及び製品を作出する組成物及び方法
GB201602145D0 (en) 2016-02-05 2016-03-23 Achieve Pharma Uk Ltd Salt
US10897925B2 (en) 2018-07-27 2021-01-26 Joseph Pandolfino Articles and formulations for smoking products and vaporizers
US20200035118A1 (en) 2018-07-27 2020-01-30 Joseph Pandolfino Methods and products to facilitate smokers switching to a tobacco heating product or e-cigarettes
WO2022264621A1 (fr) * 2021-06-15 2022-12-22 日本たばこ産業株式会社 Composition de tabac

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DATABASE WPI Derwent World Patents Index; AN 80-28065c, XP002005722 *

Also Published As

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AU5091896A (en) 1996-09-23

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